Global gene expression profiling and histochemical analysis of the developing human fetal pancreas

Sarkar, Sagartirtha; Kobberup, Sune; Wong, Randall; Lopez, Ana D.; Quayum, Nayeem; Still, T.; Kutchma, Alecksandr; Jensen, Jens Fog; Gianani, Roberto; Beattie, G M; Jensen, Jan; Hayek, Alberto; Hutton, John C.

doi:10.1007/s00125-007-0880-0

Cited by 87 publications

(96 citation statements)

References 40 publications

(39 reference statements)

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“…It was found in occasional early, but not later, glucagon-producing cells (Jeon et al, 2009). Ngn3 þ cells are found scattered in the epithelium at G9w, concomitant with the emergence of b-cells first at G8w, which are followed by a-cells and dcells at G9w (Polak et al, 2000;Sarkar et al, 2008;Jeon et al, 2009). A rare population (<5%) of insulin þ / glucagon þ cells was also reported in the early human fetal pancreas.…”

Section: Developmental Dynamicsmentioning

confidence: 81%

“…A rare population (<5%) of insulin þ / glucagon þ cells was also reported in the early human fetal pancreas. In contrast to the mouse primary transition, there seem to be few if any distinct first-wave endocrine cells found in human, and it therefore seems difficult currently to assume that there is a human equivalent of the mouse secondary transition, either in terms of morphology or any dramatic changes in endocrine-specific transcription regulator expression (Sarkar et al, 2008); there may be a single, extended transition. Nevertheless, the insitiation of exocrine differentiation at G11w could represent the beginning of the move to a human secondary transition, classifying on the basis of the emergence of the cell-specific differentiation programs.…”

Section: Developmental Dynamicsmentioning

confidence: 99%

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Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

514

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Section: Developmental Dynamicsmentioning

confidence: 81%

Section: Developmental Dynamicsmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

514

594

View full text Add to dashboard Cite

show abstract

“…Recently, a series of elegant studies using immunohistochemistry and gene expression profiling has suggested the presence of an undifferentiated islet precursor cell population in the developing human pancreas (17). However, so far, most studies on foetal pancreas development have been carried out in relatively small numbers of cases, and the growth patterns of the endocrine pancreas have not yet been analysed throughout the entire prenatal period (15,16,18,19).…”

Section: Introductionmentioning

confidence: 99%

β-cell development and turnover during prenatal life in humans

Meier

Köhler²,

Alkhatib³

et al. 2010

European Journal of Endocrinology

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Introduction: b-cell regeneration is an area under active investigation for the future treatment of diabetes, but little is known about the patterns and dynamics of prenatal b-cell development in humans.In particular, the quantitative changes in b-cell mass in the developing pancreas have not been elucidated in detail. We addressed the following questions in prenatal humans: i) what is the timing of b-cell occurrence and islet growth? ii) What are the dynamics of b-cell replication and apoptosis? Methods: Pancreatic tissue was obtained from 65 human embryos and foetuses aged between 8 weeks post conception (p.c.) and birth. Sections were stained for insulin, glucagon, Ki67 (proliferation marker), TUNEL (apoptosis marker) and CD31 (blood vessel marker), and morphometric analyses were performed. Results: b-cells were detected from gestational week 9 onward, whereas glucagon expression was detected already at week 8. The fractional b-cell area of the pancreas increased in a linear fashion until birth (rZ0.60, P!0.001). The first endocrine cells were found within or adjacent to the primitive ductal epithelium. b-cell replication was readily detected in the newly forming islets already starting at week 9 p.c. (average frequency 2.8G0.4%). A small percentage of cells co-expressed insulin and glucagon during the early foetal period. There was a close relationship between the development of endocrine islets and blood vessels during all stages of prenatal pancreas development suggesting a possible interaction between both cell types. The frequency of b-cell apoptosis was relatively high throughout all ages (1.5G0.3%). Conclusions: b-cell differentiation in humans occurs from week 9 p.c. onward. The first endocrine cells are closely associated with the ductal epithelium suggesting differentiation from precursor cells. High rates of b-cell replication suggest that this mechanism plays an important role in the prenatal expansion of b-cell mass.

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“…However, nuclear localized beta-cell specific MAFA expression was observed again in the adult human pancreas, similar to that observed in the mouse [80]. In contrast to these findings, another study found MAFA transcripts increased from W9, with expression maintained until at least W23, albeit at levels lower than those found in the adult [92]. Collectively, these two studies raise the possibility that expression of MAFA may be modulated at both the transcriptional and post-transcriptional level during human pancreatic development.…”

Section: Step 3: Pancreatic Endoderm To Endocrine Precursor Cellsmentioning

confidence: 51%

Derivation of Insulin-Producing Beta-Cells from Human Pluripotent Stem Cells

et al. 2014

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■ AbstractHuman embryonic stem cells have been advanced as a source of insulin-producing cells that could potentially replace cadaveric-derived islets in the treatment of type 1 diabetes. To this end, protocols have been developed that promote the formation of pancreatic progenitors and endocrine cells from human pluripotent stem cells, encompassing both embryonic stem cells and induced pluripotent stem cells. In this review, we examine these methods and place them in the context of the developmental and embryological studies upon which they are based. In particular, we outline the stepwise differentiation of cells towards definitive endoderm, pancreatic endoderm, endocrine lineages and the emergence of functional beta-cells. In doing so, we identify key factors common to many such protocols and discuss the proposed action of these factors in the context of cellular differentiation and ongoing development. We also compare strategies that entail transplantation of progenitor populations with those that seek to develop fully functional hormone expressing cells in vitro. Overall, our survey of the literature highlights the significant progress already made in the field and identifies remaining deficiencies in developing a pluripotent stem cell based treatment for type 1 diabetes.

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Global gene expression profiling and histochemical analysis of the developing human fetal pancreas

Cited by 87 publications

References 40 publications

Pancreas organogenesis: From bud to plexus to gland

Pancreas organogenesis: From bud to plexus to gland

β-cell development and turnover during prenatal life in humans

Derivation of Insulin-Producing Beta-Cells from Human Pluripotent Stem Cells

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